Animal models for nicotine dependence are critical for investigating molecular mechanisms associated with this addiction. The mouse is a tractable model that allows for dissection of these mechanisms at a level not afforded by human studies. In particular, genetically-altered mice can be used to analyze a variety of complex functions including those associated with addiction. A variety of drugs of abuse, such as morphine, cocaine and more recently nicotine, have been shown to activate the transcription factor CREB (CAMP response element binding protein) in the brain. We will utilize mice homozygous for a targeted mutation in CREB (CREBaD mutant mice) to test the hypothesis that CREB is a central signaling molecule required for the addictive properties of nicotine. We will test this central hypothesis in three specific aims. First, we will investigate if activation of the transcription factor CREB is critical for the manifestation of rewarding effects of nicotine using a conditioned place preference paradigm (CPP) for nicotine in wild type and CREBaD mutant mice. Next, we will determine if CREB is critical for the manifestation of aversive effects of nicotine withdrawal and/or the underlying mechanism responsible for the maintenance of nicotine reward. We will treat wild type and CREBaD mutant mice with nicotine and evaluate both physical (somatic signs) and psychological (conditioned place aversion) signs of withdrawal. Furthermore, the effects of a withdrawal period on subsequent rewarding properties of nicotine will also be evaluated. Lastly, we will establish if the rewarding properties of nicotine are mediated through the endogenous opioid system, and if this occurs in a CREB dependent manner. We will utilize the opioid receptor antagonist naloxone, as well as mv-opioid receptor knock-out mice to evaluate changes in CREB activation and behavioral responses in conditioned place preference following acute and chronic nicotine administration. Together, these studies will provide insights into the molecular mechanisms underlying nicotine reward as well as interactions between nicotine and the endogenous opioid system. The complete understanding of these mechanisms would open new perspectives for the successful treatment of nicotine addiction.